Major depressive disorder (MDD) is a debilitating disorder of altered mood regulation. Despite the substantial financial and emotional burden of MDD, understanding the pathological and molecular features of this disorder remains a considerable challenge in neuropsychiatry research. One major risk factor for depression is sex: one in four women, but only one in ten men, will experience a debilitating episode of MDD in the course of a lifetime. A past limitation to investigate this major risk factor and associated mechanisms was the lack of an animal model that not only mimics the complexity of the disorder but also replicates the female vulnerability. In addition to mimicking symptom dimensions, antidepressant reversal, and molecular profile characteristics of human MDD, we now show that unpredictable chronic mild stress (UCMS) in mice recapitulates the female differences in emotionality and vulnerability to depression, making UCMS the appropriate model to investigate underlying mechanisms involved in sex differences in MDD. Emotionality is defined as measured parameters for rodent behavior and physiology that are homologous to human emotions. Although evidence suggests a partial contribution of circulating sex hormones to female emotionality, this proposal aims to use the UCMS model to test the alternative and less investigated hypothesis of a developmental origin of the sexual dimorphism of emotionality and vulnerability to depression. Studies in human subjects and in rodent models suggest a developmental origin for mood disorders. Interestingly, a developmental process also establishes sex differences in the brain, as developmental exposure to testosterone permanently masculinizes the structure of several brain regions, including the amygdala. This project will 1) determine whether developmental organization of the male/female brain (through postnatal testosterone exposure) underlies adult sex differences in baseline and/or stress induced emotionality in mice, and 2) determine whether the developmentally determined molecular correlates underlying altered emotionality in female mice predict similar changes in human female MDD subjects and are reversed by developmental testosterone treatment. PUBLIC HEALTH RELEVANCE: If gender differences in major depression are due to underlying biological sex differences, a better understanding of the biology is warranted to develop better treatment or even prevention of major depression. One major problem with studying depression in rodents has been the lack of models that replicate the well documented human female vulnerability to depression. Importantly, the Sibille lab now shows that the unpredictable chronic mild stress mouse model recapitulates the female vulnerability to major depression, and thus, the proposed studies will use this model to investigate possible biological causes for sex differences in depression.